RESUMO
[This corrects the article DOI: 10.1371/journal.ppat.1008140.].
RESUMO
Diabetes is a significant risk factor for the development of active tuberculosis. In this study, we used a mouse model of type 2 diabetes mellitus (T2DM) to determine the effect of prior Bacillus Calmette-Guérin (BCG) vaccination on immune responses to Mycobacterium tuberculosis (Mtb) infection. We found that, at 6-7 months after Mtb infection, 90% of the Mtb-infected T2DM mice died, whereas only 50% of BCG-vaccinated T2DM-Mtb-infected mice died. Moreover, 40% of the PBS-treated uninfected T2DM mice and 30% of the uninfected BCG-vaccinated T2DM mice died, whereas all uninfected and infected nondiabetic mice survived. BCG vaccination was less effective in reducing the lung bacterial burden of Mtb-infected T2DM mice compared with Mtb-infected nondiabetic mice. BCG vaccination significantly reduced lung inflammation in Mtb-infected T2DM mice compared with that of unvaccinated T2DM mice infected with Mtb. Furthermore, reduced mortality of BCG-vaccinated Mtb-infected T2DM mice is associated with expansion of IL-13-producing CXCR3+ Tregs in the lungs of Mtb-infected T2DM mice. Recombinant IL-13 and Tregs from BCG-vaccinated Mtb-infected T2DM mice converted proinflammatory M1 macrophages to antiinflammatory M2 macrophages. Our findings suggest a potentially novel role for BCG in preventing excess inflammation and mortality in T2DM mice infected with Mtb.
Assuntos
Vacina BCG/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Tuberculose/mortalidade , Animais , Vacina BCG/imunologia , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Tuberculose/complicações , Tuberculose/imunologia , Tuberculose/prevenção & controleRESUMO
CD4+CD25+FoxP3+ cells (Tregs) inhibit inflammatory immune responses to allografts. Here, we found that co-transplantation of allogeneic pancreatic islets with Tregs that are defective in c-Jun N-terminal kinase 1 (JNK1) signaling prolongs islet allograft survival in the liver parenchyma of chemically induced diabetic mice (CDM). Adoptively transferred JNK1-/- but not wild-type (WT) Tregs survive longer in the liver parenchyma of CDM. JNK1-/- Tregs are resistant to apoptosis and express anti-apoptotic molecules. JNK1-/- Tregs express higher levels of lymphocyte activation gene-3 molecule (LAG-3) on their surface and produce higher amounts of the anti-inflammatory cytokine interleukin (IL)-10 compared with WT Tregs. JNK1-/- Tregs inhibit liver alloimmune responses more efficiently than WT Tregs. JNK1-/- but not WT Tregs are able to inhibit IL-17 and IL-21 production through enhanced LAG-3 expression and IL-10 production. Our study identifies a novel role of JNK1 signaling in Tregs that enhances islet allograft survival in the liver parenchyma of CDM.